Cancer is a broad group of various diseases, all involving uncontrolled cell growth. According to GLOBOCAN, on 2012 the number of new cases of cancer is estimated at 14.1 million and the number of death caused by cancer is estimated at 8.2 millions. In comparison, said numbers were estimated respectively at 12.7 and 7.6 millions in 2008. In 2008, cancer represented about 10% of total human deaths worldwide. Rates are rising while intensive investigations and researches for new therapeutic strategies are ongoing.
Several various therapeutic strategies have been proposed for overcoming cancer. One of them involves the MAP Kinase/ERK (Extracellular-signal Regulated) pathway and its inhibition, which is investigated in the hope of developing a new anticancer drug.
It has been shown that cancers are frequently associated with an aberrant activation of the ERK pathway. This is due to mutations encountered in a variety of malignancies that lead to an over-activation of Ras or Raf proteins upstream from ERK. Consequently, the inhibition of this pathway is intensely pursued as therapeutics.
However, targeting this pathway is challenging since ERK plays an essential role in homeostatic functions. This is probably due to the large number of distinct and even opposing cellular responses that are regulated by ERK. It follows that very few anticancer drugs targeting the ERK pathway have been validated at the clinical level for treating cancer. Indeed, the currently available ERK inhibitors act on the kinases upstream from ERK, including Raf or MEK, and as such act as total inhibitors of ERK activity towards all its substrates, without discrimination. This results in non-specific and important toxic side effects on cellular homeostasis, which is unacceptable in the treatment of patients suffering from cancer.
There is thus an unfulfilled need for new anti-cancer agents, which could efficiently target the ERK pathway, while being effective and having less undesirable side-effects.
The inventors have previously developed new strategies to overcome this challenge by targeting more specifically targets of interest downstream from ERK, rather than upstream of ERK. As disclosed in WO 2006/087242, the inventors have developed cell penetrating peptides that comprise an amino-acid sequence corresponding to the docking domain of a given substrate onto the kinase ERK (Extracellular-signal Regulated Kinase). Said peptides thus selectively interfere with either the DEJL or the DEF docking sites for ERK towards each of its substrates. Such specificity can be provided by the docking sites of ERK, which are necessary to provide selective recognition, interaction and phosphorylation of its substrates.
The DEF-domain docking site (Docking site for ERK, FXFP) is responsible for the binding of active ERK towards nuclear substrates, which are necessary for cell cycle progression. Another distinct domain is the D domain (or DEJL: Docking site for ERK and JNK, LXL), which is required for the recognition and activation of ERK effectors or kinases, such as Rsk or MSKs, but also ERK inhibition by its phosphatases (MKPs), or recognition and activation by MEKs.
The peptides previously developed by the inventors act downstream from ERK as selective inhibitors of one, and only one, ERK substrate. Their biological effects are thus more targeted and not toxic.
These peptides represent a new type of inhibitors that selectively impacts one target downstream of ERK, but leaves intact the global activity of ERK. This concept is based on the ability of ERK to bind to its downstream targets via specific docking domains, the DEJL and the DEF docking sites for ERK, that are crucial for the recognition, interaction and phosphorylation of substrates by activated ERK.
The inventors have designed a very specific peptide, namely TAT-DEF-c-Fos, to interfere with the interaction between ERK and the proto-oncogene c-Fos. This interaction is specific of the DEF domain, and leads to c-Fos phosphorylation, an important event for its stabilization and oncogenic properties. c-Fos is an immediate early gene, critically involved in cell transformation, highly expressed in different cancers, and is a pronostic marker of cancer progression.
Importantly, while there is increased amount of c-Fos expression in tumorigenic cells, c-Fos itself is rarely mutated in cancer, requiring dysfunction of the Ras/ERK signalling pathways for abnormal activity. c-Fos is also involved in the transition of tumorigenic cells into invasive and metastatic cells.
Surprisingly, the inventors have thus shown that the TAT-DEF-c-Fos, has anti-proliferative and anti-invasive properties on specific human cell lines.
Therefore, they developed a highly promising therapeutic strategy on pathologies associated with aberrant cell proliferation and invasion including cancers and metastasis.